The primary objective of this career development award application is to provide me with the proper mentored environment to progress and develop into a successful independent researcher in risk factors for progression in esophageal neoplasia. The incidence of esophageal cancer, particularly adenocarcinoma, is rising rapidly in western countries, and the large majority of esophageal cancer patients die from complications of metastatic disease. However, factors that affect site-specific metastasis have not been well described. Our preliminary research indicates that, in patients with esophageal cancer, smoking may increase the risk of lung metastasis, while alcohol significantly reduces the risk of liver metastasis. The specific aims of the research proposal are to: (1) determine whether smoking increases the risk of lung metastasis from esophageal cancer; (2) determine whether alcohol decreases the risk of liver metastasis from esophageal cancer; and (3) determine whether smoking and alcohol impact site-specific metastatic risk via effects on the primary tumor (the seed), the site of metastasis (the soil), or both. In order to accomplish Aims 1 and 2, I propose to conduct a nested case-control study from a cohort of esophageal cancer patients to confirm the site-specific effects of smoking and alcohol on patterns of metastasis. Cases will be defined as esophageal cancer patients with lung or liver metastases, and controls as those patients without lung or liver metastases. In order to accomplish Aim 3, exploratory analyses will be performed of the primary tumor and of sites of metastasis. Primary tumor tissue will be analyzed for expression of high mobility group proteins Al and A2, potential markers of metastatic behavior. Lung damage will be quantified by forced expiratory volume (one second) and by the major urinary prostaglandin-E2 metabolite, an experimental measure of tobacco-induced lung injury. Liver fibrosis will be estimated using an algorithm comprised of three serum markers (hyaluronic acid, procollagen III, and TIMP-1). The identification of lifestyle risk factors for site-specific metastasis and their site of action (seed or soil) will: improve predictive modeling of patients at risk for spread of esophageal cancer; identify novel targets for future chemopreventive and therapeutic agents; and serve as a model to study risk factors for site-specific metastasis.